DESCRIPTION: (Verbatim from the Applicant's Abstract) The relationship between alpha-synuclein, Lewy body-like inclusions and nigrostriatal degenerated will be evaluated using transgenic mice in which the human wild-type or mutant (A53T) forms of alpha-synuclein are overexpressed under the tyrosine hydroxylase promoter. The first hypothesis to be tested is that overexpression of human alpha-synuclein itself leads to neurodegenerative changes. Changes in the number o dopaminergic neurons in the substantia nigra, alterations in striatal dopaminergic terminals, and the possible formation of Lewy body-like inclusions will be compared in overexpressing mice vs. controls of different ages. The second hypothesis is that overexpression of alpha-synuclein increases the vulnerability f the nigrostriatal system to neurotoxic injury. Mice will be exposed to MPTP, 6-hydroxydopamine, or methamphetamine, and assessed for cell damage and inclusion body formation in the nigrostriatal system The third hypothesis is that an impairment of proteasome activity play a role in alpha-synuclein aggregation and consequent neurodegeneration. The effects of proteasome inhibition the formation of Lewy body-like inclusions will be compared in mice overexpressing alpha-synuclein vs. nonoverexpressing controls in the presence and absence of neurotoxic exposure. Results of these experiments should help to elucidate the mechanism of alpha-synuclein-induced neurodegeneration in familial and sporadic cases of human Parkinsonism. Transgenic mice overexpressing alpha-synuclein are also likely to be a suitable model for studying the mechanism of formation and role of Lewy body-like inclusions in nigrostriatal degeneration. Finally, findings could provide clues s to why the aging nigrostriatal system becomes more susceptible to neurodegeneration.